rs56248469

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000875.5(IGF1R):c.1784G>A(p.Arg595His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,140 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.12

Variant links:

Genes affected

IGF1R (HGNC:5465): (insulin like growth factor 1 receptor) This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

IGF1R links:

IGF1R (HGNC:):

IGF1R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGF1R. . Trascript score misZ 4.6449 (greater than threshold 3.09). GenCC has associacion of gene with growth delay due to insulin-like growth factor I resistance.

BP4

Computational evidence support a benign effect (MetaRNN=0.018484533).

BP6

Variant 15-98913238-G-A is Benign according to our data. Variant chr15-98913238-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284570.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00067 (102/152288) while in subpopulation NFE AF= 0.00125 (85/68026). AF 95% confidence interval is 0.00103. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5 linkuse as main transcript	c.1784G>A	p.Arg595His	missense_variant	8/21	ENST00000650285.1	NP_000866.1	P08069

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IGF1R	ENST00000650285.1 linkuse as main transcript	c.1784G>A	p.Arg595His	missense_variant	8/21		NM_000875.5	ENSP00000497069.1	P08069
IGF1R	ENST00000559925.5 linkuse as main transcript	n.1784G>A		non_coding_transcript_exon_variant	8/10	1
IGF1R	ENST00000649865.1 linkuse as main transcript	c.1784G>A	p.Arg595His	missense_variant	8/21			ENSP00000496919.1	C9J5X1
IGF1R	ENST00000560144.1 linkuse as main transcript	n.62G>A		non_coding_transcript_exon_variant	1/4	3		ENSP00000456950.1	H3BSZ8

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000644

AC:

162

AN:

251468

Hom.:

AF XY:

0.000633

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00154

AC:

2253

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1086

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00196

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152288

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000748

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000626

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2023	Reported in the heterozygous state in a patient with isolated craniosynostosis (PMID: 21204214); Functional studies conducted on a cell line derived from the previously published patient harboring this variant, showed increased IRS1 and GSK3 phosphorylation; however additional studies are needed to validate the functional effect of this specific variant (PMID: 23073384); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23073384, 21204214) -

Growth delay due to insulin-like growth factor I resistance

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.37

T;.;T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.94

.;.;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

N;.;N;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

1.1

.;.;N;N

REVEL

Benign

0.13

Sift

Benign

0.54

.;.;T;T

Sift4G

Benign

0.56

.;.;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.18, 0.17

MVP

0.63

MPC

0.77

ClinPred

0.022

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over